PROJECT SUMMARY This proposal describes a five-year career development program to prepare Dr. David Marciano for a career as an independent investigator. This program builds on Dr. Marciano?s extensive background as a molecular pharmacologist by providing him with the training to establish expertise in extracellular vesicle biology, in vivo surgery, state-of-the-art imaging and iPSC to investigate new therapeutic strategies to treat pulmonary arterial hypertension (PAH). Dr. Marciano?s primary mentor is Dr. Michael Snyder, a Professor and chair of the Genetics department at Stanford University and his Co-mentor Dr. Marlene Rabinovitch is a clinical professor in the pediatrics department and expert in PAH. Drs. Snyder and Rabinovitch have a long standing collaboration and are excellent mentors with many former trainees now established as independent investigators. The K99 phase of Dr. Marciano?s studies will focus on supporting his investigation into the role of BMPR2 in mediating the hypoxic cellular response and its dysfunction in PAH. Specifically, in AIM 1 of Dr. Marciano?s proposal he seeks to determine the therapeutic potential of BMPR2 enriched extracellular vesicles (EV) in reversing disease progression. The therapeutic application of EV is an emerging field that Dr. Marciano is being trained in as a future leader. In AIM 2 of Dr. Marciano?s proposal he will investigate the effect of laminar shear-stress, the frictional force of blood flow on EV signaling. He will apply live PET imaging to track the bioidistriubtion of EV and the effect of different cellular perturbations on their targeting. In Aim 3 of the proposed studies, Dr. Marciano will initiate studies towards the development of autologous ?personalized? EV derived from a patient?s own stem cells as a strategy to reduce adverse immune reactions. Dr. Marciano is uniquely positioned to leverage his background in translational medicine to extend the exciting preliminary findings from which this proposal builds to identify new PAH therapies. This work will also provide the foundation for future studies, which will be carried out by Dr. Marciano as an independent investigator.